Peds1-KO Mouse

Peds1, also known as plasmanylethanolamine desaturase 1 (TMEM189), is an enzyme crucial for plasmalogen biosynthesis. Plasmalogens are glycerophospholipids with a vinyl ether bond, which endows them with unique properties. Peds1 introduces the characteristic 1-O-alk-1'-enyl double bond in the final step of plasmalogen synthesis [2,4]. Plasmalogens have proposed roles in membrane organization, fluidity, signaling, and antioxidative functions, and abnormal levels are associated with various human pathologies [2].

Peds1-deficient zebrafish larvae display delayed development, increased basal inflammation, normal hematopoietic stem and progenitor cell emergence, and cell-autonomous myeloid cell apoptosis. In inflammation models, they show impaired inflammation resolution and tissue regeneration, increased interleukin-1β and NF-κB expression, and elevated ROS levels at the wound site. Chronic skin inflammation worsens in these larvae but can be mitigated by exogenous plasmalogen. Pharmacological inhibition of caspase-3 and colony-stimulating factor 3-induced myelopoiesis also alleviates hyper-susceptibility to bacterial infection [1]. Peds1-knockout mice have a growth phenotype, with a strong reduction of plasmenyl lipids and a massive accumulation of plasmanyl lipids in analyzed tissues, except for phosphatidylethanolamines where total levels remain constant. The rate-limiting enzyme in ether lipid metabolism, FAR1, is not upregulated in these mice, indicating no activation of the feedback mechanism seen in total ether lipid deficiency [3].

In conclusion, Peds1 is essential for plasmalogen biosynthesis. Through gene-knockout models in zebrafish and mice, it has been shown to play a significant role in myeloid cell biology, inflammation, and lipid metabolism. These findings contribute to understanding its implications in related disease conditions such as abnormal inflammation and potentially in diseases associated with altered plasmalogen levels [1,3].

References:

1. Arroyo, Ana B, Tyrkalska, Sylwia D, Bastida-Martínez, Eva, Elías-Arnanz, Montserrat, Mulero, Victoriano. 2024. Peds1 deficiency in zebrafish results in myeloid cell apoptosis and exacerbated inflammation. In Cell death discovery, 10, 388. doi:10.1038/s41420-024-02141-w. https://pubmed.ncbi.nlm.nih.gov/39209813/

2. Padmanabhan, S, Monera-Girona, Antonio J, Pajares-Martínez, Elena, Fontes, Marta, Elías-Arnanz, Montserrat. 2022. Plasmalogens and Photooxidative Stress Signaling in Myxobacteria, and How it Unmasked CarF/TMEM189 as the Δ1'-Desaturase PEDS1 for Human Plasmalogen Biosynthesis. In Frontiers in cell and developmental biology, 10, 884689. doi:10.3389/fcell.2022.884689. https://pubmed.ncbi.nlm.nih.gov/35646900/

3. Lackner, Katharina, Sailer, Sabrina, van Klinken, Jan-Bert, Werner, Ernst R, Watschinger, Katrin. 2023. Alterations in ether lipid metabolism and the consequences for the mouse lipidome. In Biochimica et biophysica acta. Molecular and cell biology of lipids, 1868, 159285. doi:10.1016/j.bbalip.2023.159285. https://pubmed.ncbi.nlm.nih.gov/36690320/

4. Werner, Ernst R, Fernández-Quintero, Monica L, Hulo, Nicolas, Liedl, Klaus R, Watschinger, Katrin. 2022. Essential role of a conserved aspartate for the enzymatic activity of plasmanylethanolamine desaturase. In Cellular and molecular life sciences : CMLS, 79, 214. doi:10.1007/s00018-022-04238-w. https://pubmed.ncbi.nlm.nih.gov/35347434/